Motilin is a physiologically active peptide of 22 amino acids isolated from the abdominal smooth muscle and its structure was first identified in 1973 by isolation of porcine motilin (Non-Patent Documents 1 and 2). In 1995, human motilin was isolated and identified to have the same structure as the porcine motilin (Non-Patent Document 3).
Motilin is known to have a physiological function that is associated with the interdigestive migrating complex (hereinafter abbreviated as IMC) which occurs in a fasting stage. IMC is a physiological function by which the contents of the gastrointestinal tract such as the epithelium and mucous membrane that have been peeled off from its internal wall, as well as the secretory fluids therefrom are forced to flow down to its lower part, thereby cleaning up its interior. In healthy persons, motilin is secreted from the duodenum and jejunum at approximately 100-min intervals in a fasting stage, with IMC occurring with an increase in the plasma motilin level (Non-Patent Document 4); IMC is induced when motilin is administered to a dog, monkey, or a human (Non-Patent Documents, 5, 6 and 7); physiological IMC occurrence is suppressed by administering anti-motilin serum; in view of these and other findings, it is held that gastrointestinal functions such as the digestion of foods and the secretion of digestive juice are maintained normally as the result of motilin secretion which induces IMC, causing the debris to be removed from within the gastrointestinal tract (Non-Patent Document 8).
Regarding the relations between IMC abnormality and a disease, it has been reported that, when IMC is reduced, the debris within the gastrointestinal tract accumulates within the intestinal tract to cause an abnormal growth of intestinal bacteria, whereupon endotoxins are produced by the intestinal bacteria to induce gastrointestinal conditions such as excessive evolution of gas, abdominal bloating, diarrhea, and abdominal pain (Non-Patent Document 9). Particularly in diseases that are associated with functional abnormalities in the gastrointestinal tract, such as functional dyspepsia, post-operative ileus, and chronic idiopathic intestinal pseudo-obstruction, it has been reported that IMC occurrence is reduced or not observed at all (Non-Patent Document 13) and that a decrease in the secretion of endogenous motilin in vivo or a decrease in the motilin action is related to abnormalities or reduction in the gastrointestinal motility functions (Non-Patent Document 14). Irritable bowel syndrome is a chronic intestinal disorder which, in the absence of any underlying diseases such as inflammations and tumors but on account of functional abnormalities in the lower gastrointestinal tract, typically the large intestine, causes chronic abdominal discomfort as exemplified by abdominal pain and abdominal bloating, or bowel movement abnormalities such as constipation and diarrhea. It has been reported that in at least some of the patients who developed irritable bowel syndrome, the intestinal flora had altered to cause a change in bacterial species, abnormal bacterial growth, etc. (Non-Patent Document 9) and the accumulation of the gastrointestinal debris within the intestinal tract on account of reduced occurrence of IMC may be a cause of the change in the intestinal flora.
The currently available drugs of first choice against diseases associated with the aforementioned functional abnormalities in the gastrointestinal tract are medicines for internal use to improve gastrointestinal motility function, as exemplified by dopamine receptor antagonists, selective serotonin 5-HT4 receptor agonists, and parasympathetic stimulating agents. There are indeed some cases where treatment with these therapeutic drugs showed a temporary improvement of the symptoms but in many other cases, no therapeutic effect was observed and doctors and patients are getting only low satisfaction from those internal medicines used to improve gastrointestinal motility. Therefore, it is strongly desired to provide therapeutics based on a new mechanism of action and it is expected to lead to amelioration of the symptoms or curing of the disease by externally administering motilin receptor agonists to patients with functional abnormalities in the gastrointestinal tract so as to normalize their gastrointestinal functions.
Ever since it was reported that erythromycin and its related compounds have an activity as motilin agonists, clinical trials have been conducted with low-molecular weight motilin agonists on patients with functional abnormalities in the gastrointestinal tract (Non-Patent Documents 19 and 20) and there are also a plurality of such low-molecular weight motilin agonists that were subjected to clinical trials as oral drugs (Non-Patent Documents 21 and 22). However, for one or another reason such as the development of side-effects that have nothing to do with the action as motilin agonists (i.e., HERG inhibition, spermatogenic defect, and carcinogenic effect) or the attenuation of the drug efficacy due to repeated administration, the development of pharmaceuticals containing the motilin agonists as the active ingredient has been suspended and none of them have so far been put on the market as medicines for improving gastrointestinal functions.
Clinical trials were also performed on patients with functional abnormalities in the gastrointestinal tract, using native motilin or peptide motilin agonists as peptide compounds (Non-Patent Documents 15 and 16). However, the only route of administration that has ever been reported in connection with the clinical trials and animal experiments using these peptide compounds is an intravenous one and on account of the difficulty in realizing prolonged, repeated administration to patients, the therapeutic efficacy of the compounds is yet to be verified.
Examples of motilin-like peptide compounds that have so far been developed are atilmotin of Baxter (Patent Document 1) and SK-896 of SANWA KAGAKU (Patent Document 2). The former is a compound created with a view to improving the in vivo half-life and by means of a metabolism experiment using a homogenate supernatant of the kidney which is conceived as a primary organ for motilin metabolism (Non-Patent Document 17), the compound has been verified to have better metabolic stability (Patent Document 1) and its half-life in plasma is about 10 minutes, approximately three times as long as that of motilin (Non-Patent Document 18). The latter is a compound designed to realize more efficient production. Both compounds maintain a gastrointestinal motility enhancing activity comparable to that of motilin. However, as in the case of motilin, the route of administration of these compounds is limited to an intravenous one and each compound has the problem that its use is limited to the treatment in medical facilities where it cannot be used for a prolonged period of time. Hence, there has been accomplished no drug discovery that is based on the inherent action of motilin, i.e., maintaining the gastrointestinal functions in a normal way by removing the debris from the inside of the gastrointestinal tract, with the result that the therapeutic efficacy of either compound is yet to be verified.
A peptide having a substitution of leucine for methionine at position 13 of motilin has been developed (Patent Document 3). However, the biological activity of this peptide is comparable to that of motilin and the route of its administration is limited to an intravenous one, thus leaving the problem of impossibility of prolonged use still unsolved.
In view of the foregoing, it is desired that in order to develop a novel therapeutic drug based on the inherent action of motilin, a peptidic motilin agonist should be provided as a pharmaceutical agent that can be administered for a prolonged period of time via a noninvasive route.